Journal
AGE
Volume 35, Issue 3, Pages 673-687Publisher
SPRINGER
DOI: 10.1007/s11357-012-9403-0
Keywords
Alzheimer's disease; Pyroglutamate amyloid beta; Lysosomal pathology
Categories
Funding
- European Commission [37670, 212043]
- Internationale Stichting Alzheimer Onderzoek Nederland (ISAO) [07506]
- Netherlands Organisation for Scientific Research (NWO) [836.05.060]
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Deposition of aggregated amyloid beta (A beta) is a major hallmark of Alzheimer's disease (AD)-a common age-related neurodegenerative disorder. Typically, A beta is generated as a peptide of varying lengths. However, a major fraction of A beta peptides in the brains of AD patients has undergone posttranslational modifications, which often radically change the properties of the peptides. A beta(3(pE)-42) is an N-truncated, pyroglutamate-modified variant that is abundantly present in AD brain and was suggested to play a role early in the pathogenesis. Here we show that intracellular accumulation of oligomeric aggregates of A beta(3(pE)-42) results in loss of lysosomal integrity. Using a novel antibody specific for aggregates of A beta pE3, we show that in postmortem human brain tissue, aggregated A beta pE3 is predominantly found in the lysosomes of both neurons and glial cells. Our data further demonstrate that A beta pE3 is relatively resistant to lysosomal degradation, which may explain its accumulation in the lysosomes. The intracellular A beta pE3 aggregates increase in an age-dependent manner. The results presented in this study support a model where A beta pathology and aging converge, leading to accumulation of the degradation-resistant pE-modified A beta in the lysosomes, lysosomal dysfunction, and neurodegeneration.
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